AIM:To investigate the effects and underlying mechanisms of paeoniflorin(PF)on lipopolysac-charide(LPS)-induced intestinal injury in septic mice,using a combination of network pharmacology,molecular docking,and animal experiments.METHODS:Network pharmacology was used to identify key active components and therapeutic targets of Red Peony for treating sepsis.Molecular docking was performed to explore the binding affinity be-tween PF and silent information regulator 1(SIRT1).An LPS-induced mouse model of sepsis with intestinal injury was es-tablished.Samples were collected 24 h after modeling,and hematoxylin-eosin(HE)staining was performed to observe pathological changes in intestinal tissues.Chiu's scoring system was utilized to evaluate the extent of intestinal injury.En-zyme-linked immunosorbent assay(ELISA)was employed to measure levels of inflammatory factors in intestinal tissues,including interleukin-1β(IL-1β)and IL-18,as well as indicators of intestinal permeability such as diamine oxidase(DAO)and intestinal-type fatty acid-binding protein(I-FABP),alongside serum levels of D-lactate and the aerobic gly-colysis product L-lactate.Western blot analysis was performed to assess changes in protein levels of SIRT1,M2-type pyru-vate kinase(PKM2),and NOD-like receptor protein 3(NLRP3)in intestinal tissues.RESULTS:Network pharmacolo-gy suggested that paeoniflorin,an active component of Red Peony,treats sepsis by targeting SIRT1 among other proteins.Molecular docking revealed a strong binding affinity of PF with SIRT1.In vivo experimentation revealed significant patho-logical damage in intestinal tissues in the LPS group compared to the control group as evidenced by HE staining.Chiu's score,along with levels of IL-1β,IL-18,D-lactate,and L-lactate were significantly elevated,while DAO and I-FABP levels were reduced(P＜0.05).SIRT1 expression decreased,while PKM2 and NLRP3 levels increased(P＜0.05).In contrast,the LPS+PF group displayed reduced intestinal histopathological injury,lower Chiu's scores,and decreased levels of IL-1β,IL-18,D-lactate,and L-lactate,along with increased DAO and I-FABP levels(P＜0.05).Notably,SIRT1 protein expression increased while PKM2 and NLRP3 levels decreased(P＜0.05).Furthermore,compared to the LPS+PF group,the LPS+PF+EX527 group exhibited exacerbated intestinal histopathological injury,increased Chiu's scores,as well as elevated levels of IL-1β,IL-18,D-lactate,and L-lactate,alongside reduced DAO and I-FABP levels(P＜0.05),decreased SIRT1 expression,and increased PKM2 and NLRP3 levels(P＜0.05).CONCLUSION:Paeoni-florin effectively alleviates intestinal injury in mice with sepsis,potentially through the upregulation of SIRT1 expression and the inhibition of PKM2-mediated aerobic glycolysis,which subsequently reduces the activation of NLRP3 inflamma-somes,mitigates the release of inflammatory factors,and lessens intestinal inflammation.

AIM:To investigate the effects and underlying mechanisms of paeoniflorin(PF)on lipopolysac-charide(LPS)-induced intestinal injury in septic mice,using a combination of network pharmacology,molecular docking,and animal experiments.METHODS:Network pharmacology was used to identify key active components and therapeutic targets of Red Peony for treating sepsis.Molecular docking was performed to explore the binding affinity be-tween PF and silent information regulator 1(SIRT1).An LPS-induced mouse model of sepsis with intestinal injury was es-tablished.Samples were collected 24 h after modeling,and hematoxylin-eosin(HE)staining was performed to observe pathological changes in intestinal tissues.Chiu's scoring system was utilized to evaluate the extent of intestinal injury.En-zyme-linked immunosorbent assay(ELISA)was employed to measure levels of inflammatory factors in intestinal tissues,including interleukin-1β(IL-1β)and IL-18,as well as indicators of intestinal permeability such as diamine oxidase(DAO)and intestinal-type fatty acid-binding protein(I-FABP),alongside serum levels of D-lactate and the aerobic gly-colysis product L-lactate.Western blot analysis was performed to assess changes in protein levels of SIRT1,M2-type pyru-vate kinase(PKM2),and NOD-like receptor protein 3(NLRP3)in intestinal tissues.RESULTS:Network pharmacolo-gy suggested that paeoniflorin,an active component of Red Peony,treats sepsis by targeting SIRT1 among other proteins.Molecular docking revealed a strong binding affinity of PF with SIRT1.In vivo experimentation revealed significant patho-logical damage in intestinal tissues in the LPS group compared to the control group as evidenced by HE staining.Chiu's score,along with levels of IL-1β,IL-18,D-lactate,and L-lactate were significantly elevated,while DAO and I-FABP levels were reduced(P＜0.05).SIRT1 expression decreased,while PKM2 and NLRP3 levels increased(P＜0.05).In contrast,the LPS+PF group displayed reduced intestinal histopathological injury,lower Chiu's scores,and decreased levels of IL-1β,IL-18,D-lactate,and L-lactate,along with increased DAO and I-FABP levels(P＜0.05).Notably,SIRT1 protein expression increased while PKM2 and NLRP3 levels decreased(P＜0.05).Furthermore,compared to the LPS+PF group,the LPS+PF+EX527 group exhibited exacerbated intestinal histopathological injury,increased Chiu's scores,as well as elevated levels of IL-1β,IL-18,D-lactate,and L-lactate,alongside reduced DAO and I-FABP levels(P＜0.05),decreased SIRT1 expression,and increased PKM2 and NLRP3 levels(P＜0.05).CONCLUSION:Paeoni-florin effectively alleviates intestinal injury in mice with sepsis,potentially through the upregulation of SIRT1 expression and the inhibition of PKM2-mediated aerobic glycolysis,which subsequently reduces the activation of NLRP3 inflamma-somes,mitigates the release of inflammatory factors,and lessens intestinal inflammation.

Cancer therapy-related cardiovascular toxicity(CTR-CVT)is gradually becoming a critical factor affecting the prognosis of cancer survivors.Vascular endothelial growth factor(VEGF)and its receptor inhibitors(VEGFIs),developed as novel anti-cancer drugs targeting VEGF,are now widely used in clinical practice.They can extend the survival period of the cancer patients and improve the prognosis of the patients.However,the hypertension induced by VEGFIs,as the most common CTR-CVT,may limit and impact their use and leads to severe cardiovascular diseases(CVD).It is essential to closely monitor blood pressure in the cancer patients treated with VEGFIs,conduct early assessments,and optimize the management to achieve the best anti-cancer efficacy and minimize the risk of CTR-CVT.This review discusses the clinical manifestations,pathogenesis,diagnosis,and treatment strategies of VEGFIs-related hypertension,in order to provide better guidances for managing and addressing VEGFIs-related hypertension for the clinicians.

Lipoprotein(a)[Lp(a)]is a highly polymorphic lipoprotein molecule composed of apolipoprotein A(apo A),apo B100,and cholesterol ester core;calcific aortic valve stenosis(CAVS)is a multifactorial valvular heart disease influenced by both environmental and genetic factors.Lp(a)is an independent risk factor for CAVS and can increase the onset risk of CAVS.Lp(a)plays an important role in the treatment of CAVS.Although surgery is currently the main clinical treatment for CAVS,with further exploration into its pathological mechanism,drug therapy targeting Lp(a)has emerged as a new method.This paper reviews studies about the structure and characteristics of Lp(a),its role in the occurrence and development of CAVS,treatment options related to hyperlipoprotein Aemia,and the studies preventing and treating CAVS by combating inflammation,and enhances the clinicians'understanding and awareness of hyperlipoprotein Aemia and provides new insights for the prevention and targeted drug therapy of CAVS.

Humans ; Atrial Fibrillation/surgery* ; Left Atrial Appendage Closure ; Heart Atria/surgery* ; Catheter Ablation/methods* ; Atrial Appendage/surgery* ; Treatment Outcome

Objective:To investigate the effect in lumbar mobility and stress of the facet joint and end plate after implantation of the movable artificial lumbar spine so as to lay a biomechanical foundation for its clinical application.Methods:Total lumbar CT data of a healthy adult male were selected to construct a finite element analysis model and its effectiveness was validated (physiological group). Two groups were replicated after removing the L 3 vertebral body and adjacent discs of the model in physiological group. One group was placed with each component of the movable artificial lumbar spine to construct the non-fusion model (non-fusion group). The other group was placed with titanium cage, titanium plate and other to construct the fusion model (fusion group). The models in the three groups were loaded with 500 N axial load and 10 Nm axial load, and the torque load was used to simulate the movement in six directions: forward flexion, backward extension, left and right lateral bending, and left and right torsion. The lumbar mobility and stress peak and distribution of the proximal facet joints (J 1-2, J 4-5), L 2 inferior endplate and L4 superior endplate at the three model operating sites (L 2-3, L 3-4) and adjacent segments (L 1-2, L 4-5) under the same conditions were compared. Results:The range of motions of the surgical site in flexion, extension, left bending, right bending, left torsion and right torsion were L 2-3of 3.9°-8.7° and L 3-4 of 3.6°-8.4° in non-fusion group, significantly increased compared with fusion group (L 2-3 0.1°-0.2°, L 3-4 0.1°-0.1°) and slightly increased compared with physiological group (L 2-3 2.3°-6.0°, L 3-4 2.3°-7.1°). The range of motions of the adjacent segments in the above six directions were L 1-2 of 1.4°-4.3° and L 4-5 of 1.4°-6.0° in non-fusion group, smaller than those in fusion group (L 1-2 2.1°-6.1°, L 4-5 3.3°-8.6°) and similar to those in physiological group (L 2-3 2.3°-6.0°, L 3-4 2.3°-7.1°). The peak values of von Mises stress in the proximal facet joints were J 1-2 of 7.07-19.21 MPa and J 4-5of 6.12-12.99 MPa in non-fusion group, similar to those in physiological group (J 1-2 8.42-18.53 MPa, J 4-5 7.49-11.70 MPa) and smaller than those in fusion group (J 1-2 10.54-21.16 MPa, J 4-5 10.63-16.13 MPa). The maximum von Mises stress of the L 2 inferior endplate and L 4 superior endplate in the above six directions was 29.39-54.72 MPa and 32.31-47.87 MPa in non-fusion group, significantly increased compared with the L 2 inferior endplate (21.20-42.07 MPa), L 4 superior endplate (22.50-36.76 MPa) and L 2 inferior endplate (11.04-29.55 MPa) in fusion group and the L 4 superior endplate (13.12-21.32 MPa) in physiological group. Conclusion:Compared with the traditional fusion prostheses, the placement of the movable artificial lumbar spine can reconstruct the range of motion of the surgical site in the direction of flexion, extension, lateral bending and torsion, greatly reduce the impact on the stress of adjacent facet joints and the range of motion of adjacent segments, and theoretically reduce the incidence of prosthesis subsidence.

Acupuncture Points ; Acupuncture Therapy ; Female ; Humans ; Middle Aged ; Typhoid Fever ; diagnosis ; therapy

Objective To investigate the expression characteristics of PAK5,CyclinD1 in HCC and its relationship with clinicopathological factors and prognosis.Methods The immunohistochemical method was used to detect the expression of PAK5 and CyclinDl in 76 cases of HCC tissue and 31 cases of adjacent liver tissue.The correlation between the abnormal expression of PAK5 and CyclinD1 and clinicopathological factors and prognosis was also analyzed.Results The PAK5 expression in tumor lesions and adjacent tissue was 86.8％ (66/76) and 54.8％ (17/31) (x2 =12.962,P ＜ 0.05).Meanwhile,the CyclinD1 was positive in 73.7％ (56/76) of the HCC tissue and in 41.9％ (13/31) of the adjacent tissue (x2 =9.691,P ＜0.05).The expression of PAK5 was significantly correlated with sex (x2 =5.063,P =0.024),tumor diameter(x2 =9.159,P =0.002) and portal vein-emboli (x2 =4.469,P =0.035).CyclinD1 expression was correlated with portal vein-emboli (x2 =4.842,P =0.028),TNM (x2 =7.930,P =0.005).PAK5 expression was positively correlated with CylinD1 (γ =0.284,P =0.033).The mean survival time of PAK5positive patients after operation was shorter than the PAK5 negative patients(x2 =7.104,P =0.008).By Cox multiple factors analysis,the PAK5 expression was independent impact factors affecting the prognosis of HCC patients (RR =0.186,P =0.012).Conclusion In HCC patients positive PAK5 expression predicts poor postoperative survival.

BACKGROUND:A variety of embryonic stem cells induction and differentiation systems have been established so far, while the research that promotes embryonic stem cells to differentiate into hematopoietic stem cells is stil at an initial stage, and the induction efficiency needs to be improved.
OBJECTIVE:To active the Wnt/β-catenin signal pathway in mouse embryonic stem cells with exogenous win3a as an inducer, and then to observe whether the activation of this pathway wil promote the directional differentiation of embryonic stem cells into hematopoietic progenitor cells.
METHODS:The ES-E14TG2a mouse stem cells were cultured with the exogenous wnt3a (100 μg/L) for 21 days, the content ofβ-catenin was tested by cellimmunofluorescence and western blot, and expression of Wnt downstream target gene was detected by quantitative reverse transcription PCR to determine the activation of Wnt/β-catenin signal pathway. Single-layer adherent culture method was used to induce the directional differentiate of above-mentioned cells into hematopoietic stem cells, and detection of hematopoietic development associated surface marker CD34+/Sca-1+was achieved by flow cytometry;meanwhile, the expression of hematopoietic associated gene was measured by quantitative reverse transcription PCR.
RESULTS AND CONCLUSION:We found thatβ-catenin accumulated in ES-E14TG2a mouse stem cells after cultured with wnt3a (100 μg/L) for 21 days;the expressions of Wnt downstream target genes such as Pitx2, Frizzled, Sox17 and Oct4 showed the different degrees in increase, meaning the activation of Wnt/β-catenin signal pathway. Furthermore, during the time that we used single-layer adherent culture method to induce hematopoietic stem cells, the CD34+/Sca-1+cells accounted for 20.2%of total cells at day 14, and control cells only accounted for 11.9%. Again, expression quantity of hematopoietic associated gene BMP4, FLK2 and CD34 increased while Smad5 was suppressed significantly. Our data suggest that sustaining action by wnt3a wil active Wnt/β-catenin signal pathway, and also promote the directional differentiation of ES-E14TG2a mouse stem cells into hematopoietic progenitor cells.

Objective To study the optimum combination of orientation parameter of total hip prosthesis and acetabular safe zone on condition that the range of motion for activities of daily living (ADL) is fulfilled.Methods A three-dimensional generic parametric and visually kinematic simulation module of THA was developed.Range of motion ( ROM ) of hip flexion ≥ 110°,internal-rotation ≥30° at 90° flexion,extension ≥30° and external rotation ≥40° were defined as the normal criteria for ADL.ROM of hip flexion ≥ 120°,internal-rotation ≥45° at 90° flexion,extension ≥30° and external rotation ≥40° were as the severe criteria.The ranges of changes in general ratios (GRs) of head-neck,femoral neck antevemion ( FNA ),operative inclination (OI) and anteversion (OA) of acetabulur components were 2.0-2.92,0°-30°,10°-60°,and 0°-70° respectively.Within the limits of the upper two activity criteria,the synchronous OA of acetabulur components was calculated with every 5°change in OI of the cup,and the collodiaphyseal angle ( CDD ) was set as 135°.The safe-zone of combination of acetabulur operative anteversion (OA) and inclination (OI) was defined as the area that fulfilled the two mentioned criteria of ROM without cup-neck impingement.All parameters were analyzed by using SAS 6.12 software.Results The safe zone of acetabdar angle rose with the increase of GRs of head-neck and the safe zone of severe criteria was smaller than that of normal criteria.When the CDD angle was 135°,the sum of average aeetabular OA and acetahular OI plus 0.816 times of the FNA equaled to 84.76° innormal criteria; and the sum of average acetabular OA and acetabular OI plus 0.873 times of the FNA equaled to 92.04° in severe criteria.Conclusions A high GR of head-neck greatly increases the size of safe-zone of acetabular angle.The higher demand of ROM of hip joint requires the smaller safe zone of acetabular angle,as can be corrected by increasing the GR of head-neck.The optimum combination between the sum of average acetabular OA and acetabular OI ( Y) plus FA (X)in the normal criteria and severe criteria can be estimated by using the following formulae:Y1 =-0.816X1 + 84.76 (R2 =0.993 ),Y2 =-0.873X2 + 92.04( R2 =0.999) respectively.